Methods of treating chronic rhinosinusitis

ABSTRACT

The present invention provides methods of treating chronic rhinosinusitis that comprise administering a formulation of boric acid to the nasal and paranasal cavities of a patient in need. The present invention also provides for the use of a formulation comprising boric acid for the treatment of chronic rhinosinusitis.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.14/726,156, filed 29 May 2015, which claims the benefit under 35 U.S.C.§119(e) of U.S. Provisional Application No. 62/133,920, filed Mar. 16,2015, which applications are hereby incorporated by reference in theirentirety.

FIELD OF THE INVENTION

The present invention relates to methods for treating chronicrhinosinusitus.

BACKGROUND

Chronic Rhinosinusitis (CRS) is a persistent symptomatic inflammation ofthe nasal and paranasal sinuses characterized by at least 8-12 weeks oftwo or more symptoms selected from nasal congestion or blockage,anterior or posterior nasal discharge, facial pressure or pain, andreduction or loss of smell. CRS is further categorized based on thepresence or absence of nasal polyps (CRS without nasal polyps, CRSsNP;or CRS with nasal polyps, CRSwNP). CRSsNP is frequently associated withfacial pressure or pain, whereas CRSwNP is frequently associated with areduced ability to smell and detect odors (hyposmia). (Bachert et al.(2014) World Allergy Organ J 7(1):25; European Position Paper onRhinosinusitis and Nasal Polyps (EPOS 2012).)

CRS is considered a public health problem having a significant socialand economic impact. CRS has been variously estimated to affect from 5%to 15% of the general population, and overall annual economic burden ofCRS in the United States alone has been estimated to be $22 billion in2014. (Bachert et al., supra; Smith et al. (2015) Laryngoscope doi:10.1002/lary.25180.) Although not considered a life-threatening disease,the measurable impact of CRS on quality of life is profoundly negative,including increased sleep dysfunction, anxiety and depression inpatients having CRS. (See, e.g., Alt et al. (2013) Int Forum AllergyRhinol 3(11):941-949; Katotomichelakis et al. (2014) Int J PsychiatryMed 48(2):83-94.)

While the exact etiology of CRS has not been clearly defined, a numberof hypotheses have been considered. The mucosa lining the nasal andparanasal cavities is the interface with inhaled irritants,aero-allergens, commensal organisms, and pathogens. Because of theimportance of the epithelium as a mediator of immune defense, it hasbeen suggested that defects in a broad set of epithelium-related genescould contribute to a dysfunctional immune response to environmentalagents in patients with CRS. (Kern et al. (2008) Am J Rhinol22(6):549-559.) Diminished host defense may contribute to localmicrobial proliferation fostering the development of CRS. While the roleof microbes as causative agents in CRS is not clear, bacterial and/orfungal infection and biofilms may contribute to the propagation of CRS.(Cain and Lal (2013) Infect Drug Resist 6:1-14.) Endoscopic surgery isthe only known treatment option for effective removal of obstructivenasal polyps from CRSwNP patients; however, estimated polyp recurrencerates are unacceptably high even with use of chronic corticosteroidtherapy. (Wynn and Har-El (2004) Laryngoscope 114(5):811-813; Newton andAh-See (2008) Ther Clin Risk Manag 4(2):507-512.) Effective preventativetherapy against polyposis in CRS disease, before and after surgicalintervention, clearly remains an important unmet medical need.

Despite many decades of world-wide effort toward discovery oftherapeutic approaches against CRS, effective treatment options for thisdisease remain limited in scope and largely inadequate. While bothCRSwNP and CRSsNP are typically treated with intranasal corticosteroids(INS), second line antibiotics are often recommended in CRSsNP but areonly recommended in CRSwNP when symptoms indicate infection (pain orpurulence). Saline irrigation and oral steroids may also be recommendedwhen appropriate. (Kaplan (2013) Can Fam Physician 59(12):1275-1281.)Within the past two decades, however, and particularly since the adventof the NIH Human Microbiome Project in 2008, a large body of compellingresearch has linked inappropriate microbial colonization of theparanasal mucosa and a consequent state of chronic immuno-inflammatoryactivation to the distinctive pathophysiology of CRS. (Chalermwatanachaiet al. (2015) World Allergy Organ J 8(1):3; Hamilos (2014) J AllergyClin Immunol 33(3):640-653.) While various symptoms of CRS have all beenreported to respond favorably to chronic INS therapy, it is clear thatINS therapy can do little to resolve the underlying cause ofmicrobial-related CRS disease.

To date, no effective means of restoring host-microbial balance andmitigating disease in patients with CRS has been found. A large numberof systemic and topical bactericidal or fungicidal drugs have beenexplored in the context of CRS disease, often showing very goodshort-term efficacy for reduction of microbial density in the paranasalmucosa and concomitant alleviation of CRS clinical symptoms. (See, e.g.,Kaplan, supra; Lim et al. (2008) Am J Rhinol 22(4):381-389; Huang andGovindaraj (2013) Curr Opin Otolaryngol Head Neck Surg 21(1):31-38.)Long-term use of antibiotics is not recommended, however, due toconcerns over the danger of promoting expansion of resistant bacteria.(Kennedy and Borish (2013) Am J Rhinol Allergy 27(6):467-472.)Alternatively, clinical use of various probiotic agents and other“microbiome rebalancing” strategies has been suggested for CRS disease.(Cleland et al. (2014) Int Forum Allergy Rhinol 4(4):309-314; Mukerji etal. (2009) Otolaryngol Head Neck Surg 140(2):202-208.)

A number of alternative therapies have been postulated for CRS diseaseincluding intranasal irrigations with colloidal silver, surfactantsolutions derived from commercial baby soap products, sodiumhyaluronate, methylglyoxal, xylitol solution, and isotonic or hypertonicsaline. (Goggin et al. (2014) Int Forum Allergy Rhinol 4(3):171-175;Chiu et al. (2008) Am J Rhinol 22(1):34-37; Casale et al. (2014) Am JRhinol Allergy 28(4):345-348; Kilty et al. (2011) Int Forum AllergyRhinol 1(5):348-350; Weissman et al. (2011) Laryngoscope121(11):2468-72; van den Berg et al. (2014) Otolaryngol Head Neck Surg150(1):16-21; Ural et al. (2009) J Laryngol Otol 123(5):517-21.)Ultrasound treatment to disrupt bacterial biofilm in CRS has also beensuggested. (Ansari et al. (2012) Physiother Theory Pract 28(2):85-94;Young et al. (2010) J Laryngol Otol 124(5):495-499.)

There remains a need in the art for an effective treatment of chronicrhinosinusitis. The present invention provides an efficacious treatmentto reduce the symptoms of chronic rhinosinusitis and improve the qualityof life of those suffering from CRS. The invention also provides for theuse of a boric acid formulation for the treatment of chronicrhinosinusitis in a patient in need.

SUMMARY OF THE INVENTION

The present invention provides methods of treating chronicrhinosinusitis comprising the administration of a volume of aformulation of boric acid to the nasal and paranasal cavities of apatient in need. The present invention also provides for use of aformulation comprising boric acid for the treatment of chronicrhinosinusitis in a subject in need.

In either the method or use described and claimed herein, theformulation comprises boric acid in an amount (weight per volume, w/v)from about 1.0-4.0%, particularly from about 1.0-2.5%. In particularembodiments, the formulation comprises boric acid in an amount of about2.0% (w/v).

In various embodiments, the formulation additionally comprises a salinesolution, wherein the concentration (w/v) of sodium chloride (NaCl) inwater is from about 0.5-1.2%. In a particular embodiment theconcentration of sodium chloride in water is 0.9% (w/v), that is,isotonic saline. In one embodiment, the formulation comprises about 2%(w/v) of boric acid in a saline solution having about 0.9% (w/v) ofsodium chloride in water.

The formulation may be of a pH that is a natural result of formulatingthe desired amount of boric acid in a saline solution.

In various embodiments, the method of administering the boric acidformulation comprises applying a volume of the formulation into eachnare of the subject in need in a manner sufficient to penetrate thenasal and paranasal cavities. The volume of the formulation may beadministered by any appropriate means known to those skilled in the artand include, but are not limited to, douching, nebulization,atomization, inhalation, irrigation, spray, drops, or insufflations. Inparticular embodiments, a volume of the formulation is administered bydrops into each nare. In other particular embodiments, the volume of theformulation is applied by spray into each nare.

In a specific embodiment, the formulation is a sterile, aqueous isotonicsuspension or solution of boric acid. In another specific embodiment,the method comprises administering a volume of a formulation of sterile,aqueous isotonic suspension of boric acid intranasally to thenasal-paranasal mucosa via spray pump. In embodiments of the invention,the various methods of administration may be and often are accompaniedby maneuvering the head, and thereby the nasal and paranasal cavities,in a manner sufficient to distribute the formulation throughout thenasal and paranasal cavities. The method also may and often does includea subsequent step of clearing the nasal and paranasal cavities of excessformulation by expectoration and/or exsufflation.

In various embodiments, the volume of the formulation administered intoeach nare may vary but in all cases should be a volume sufficient tocoat the nasal and paranasal cavities. In particular embodiments, thevolume administered to each nare is about 1-2 mL. Administration isgenerally based on need and may be repeated several times per day whilesymptoms are present. In particular embodiments, formulation isadministered to the subject in need 1-3 times per day.

In all embodiments of the invention, the subject in need is a subjecthaving symptoms consistent with chronic rhinosinusitis. In someembodiments, the subject has been diagnosed as having chronicrhinosinusitis. In some embodiments, the subject having chronicrhinosinusitis may also have nasal polyps (CRSwNP). In otherembodiments, the subject having chronic rhinosinusitis does not havenasal polyps (CRSsNP). In some embodiments, the chronic rhinosinusitisis microbial-related CRS. In particular embodiments, the chronicrhinosinusitis is bacterial-related. In some embodiments, the chronicrhinosinusitis is fungal-related.

A present invention further provides a formulation comprising boric acidfor use in treating chronic rhinosinusitis. In various embodiments, theformulation comprises about 1.0-4.0% (w/v) of boric acid, moreparticularly about 2.0% (w/v) of boric acid. In some embodiments, theformulation further comprises a saline solution having about 0.5-1.2%(w/v) of sodium chloride in water, in particular a saline solutionhaving about 0.9% (w/v) of sodium chloride in water.

These and other embodiments of the subject invention will readily occurto those of skill in the art in light of the disclosure herein, and allsuch embodiments are specifically contemplated.

DETAILED DESCRIPTION OF THE INVENTION

Before the present formulations and methods are described, it is to beunderstood that the invention is not limited to the particularmethodologies, protocols, and reagents described, as these may vary. Itis also to be understood that the terminology used herein is intended todescribe particular embodiments of the present invention, and is in noway intended to limit the scope of the present invention as set forth inthe appended claims.

Each of the limitations of the invention can encompass variousembodiments of the invention. It is, therefore, anticipated that each ofthe limitations of the invention involving any one element orcombinations of elements can be included in each aspect of theinvention. This invention is not limited in its application to thedetails of construction and the arrangement of components set forth inthe following description. The invention is capable of other embodimentsand of being practiced or of being carried out in various ways. Also,the phraseology and terminology used herein is for the purpose ofdescription and should not be regarded as limiting. The use of“including,” “comprising,” or “having,” “containing,” “involving,” andvariations thereof herein, is meant to encompass the items listedthereafter and equivalents thereof as well as additional items. It mustbe noted that as used herein and in the appended claims, the singularforms “a,” “an,” and “the” include plural references unless contextclearly dictates otherwise.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the preferred methods,devices, and materials are now described. All publications cited hereinare incorporated herein by reference in their entirety for the purposeof describing and disclosing the methodologies, reagents, and toolsreported in the publications that might be used in connection with theinvention. Nothing herein is to be construed as an admission that theinvention is not entitled to antedate such disclosure.

The practice of the present invention will employ, unless otherwiseindicated, conventional methods of chemistry, biochemistry, molecularbiology, cell biology, genetics, immunology and pharmacology, within theskill of the art. Such techniques are explained fully in the literature.See, e.g., Gennaro, A.R., ed. (1990) Remington's PharmaceuticalSciences, 18th ed., Mack Publishing Co.; Hardman, J. G., Limbird, L. E.,and Gilman, A. G., eds. (2001) The Pharmacological Basis ofTherapeutics, 10th ed., McGraw-Hill Co.; Colowick, S. et al., eds.,Methods In Enzymology, Academic Press, Inc.; Weir, D. M., and Blackwell,C. C., eds. (1986) Handbook of Experimental Immunology, Vols. I-IV,Blackwell Scientific Publications.

The section headings are used herein for organizational purposes only,and are not to be construed as in any way limiting the subject matter

DEFINITIONS

The terms “disorders,” “diseases,” and “conditions” are used inclusivelyherein and refer to any condition deviating from normal.

The terms “treating,” “treatment” and the like, are used herein to meanadministering a therapy to a patient in need thereof.

An “effective amount” of a compound or formulation is an amountsufficient to bring about the desired result in a treated subject, forexample, an amount sufficient to treat chronic rhinosinusitis in asubject in need. The effective amount can vary depending upon theparticular formulation, the nature or severity of the condition beingtreated, the age, weight, etc. of the subject being treated, the routeof administration or formulation of the compound, and the dosingregimen, among other things. An effective amount can readily bedetermined by one skilled in the medical arts.

The Invention

The present invention provides methods of treating chronicrhinosinusitis that comprise administering a formulation of boric acidto the nasal and paranasal cavities of a patient in need. The presentinvention also provides for the use of a formulation comprising boricacid for the treatment of chronic rhinosinusitis.

Regardless of any palliative benefits of anti-inflammatory therapy inCRS, the present inventor has found that CRS, and in particularmicrobial-related CRS, fundamentally requires a therapeutic approachthat can safely and conveniently reduce inappropriate bacterial orfungal colonization of the human host's paranasal mucosa with minimaland tolerable side-effects.

The present invention is based on the use of a reversible, non-specificmicrobiostatic agent, which, unlike bactericidal or fungicidal enzymeinhibitors, may not readily induce adaptive resistance in microbes.Irrigation of microbe-colonized tissues with a reversible microbiostaticagent followed by a wash-out or dilution of the agent to sub-effectivelevels allows the remaining wild-type bacteria and/or fungi to continuepropagating without significant pressure to acquire drug resistance.

Although the invention is not limited to any particular mechanism ofaction (MOA), the non-specific microbiostatic agent may target suchfundamental molecular properties of microbial cell walls thatacquisition of specific resistance factors is difficult and ineffective.For example, the presence of either a thick (Gram-positive) or thin(Gram-negative) peptidoglycan sacculus is intrinsic to the bacteria ofpathogenic importance in humans. The highly-conserved repeatingdisaccharide unit, β-(1,4)-N-acetyl-D-glucosamine(GlcNAc)—O—N-acetylmuramic acid (MurNAc), comprises the helical chain ofpeptidoglycan which is further structurally modified by shortcrosslinking peptides. Each disaccharide unit of a peptidoglycan strandcontains three hydroxyl (—OH) groups that contribute to the fundamentalproperties of the helical polymer—polar R—OH groups act individually aseither hydrogen-bond donors or acceptors to create, in aggregate,functionally important secondary structure within the peptidoglycanhelix. The normal conformation, porosity, flexibility, and polarityproperties of the bacterial peptidoglycan surface could be significantlydisrupted by reversible complexation of the free hydroxyl groups ofpeptidoglycan disaccharide thus leading to temporary growth arrest.

Similarly, α- and β-glucan polysaccharides, GlcNAc polymer (chitin), andglycoproteins modified with O— and N-linked saccharides are the majorcomponents of fungal cell wall surfaces. Thus, non-specific andreversible complexation of fungal cell-surface glycoconjugates andpolysaccharides by a non-specific microbiostatic agent might similarlylead to non-lethal growth arrest in fungal pathogens.

Additionally, a non-specific microbiostatic agent may target andinterfere with mechanisms utilized by microbial agents to adhere to andcolonize the nasal and paranasal cavities. For example, because adhesionis a crucial survival factor it is not surprising that most microbialpathogens employ complex strategies against their hosts, exploitingmultiple adhesion mechanisms. For example, bacterial lectins bind withhigh specificity to cell surface saccharide motifs creating strongadhesion bonds between pathogen and host. The basic concept of blockinglectin-saccharide interactions as an approach to preventing bacterialadhesion and infection has been demonstrated in animal models. Atherapeutic agent that could reversibly and non-selectively complex withhost epithelial cell polysaccharides might effectively blocklectin-saccharide bacterial adhesion without causing either bacterial orhost-cell death.

Biofilm formation is also a common and very effective strategy formicrobial adhesion to host cell surfaces. Typical biofilms are complexmixtures of protein, polysaccharide, nucleic acids, and lipids thatprovide a mechanically stable extracellular matrix in support ofmicrobial colonization. A non-specific polysaccharide-complexing agentmight significantly destabilize biofilm matrices making them lesshospitable microbial habitats and rendering the disrupted matrix moresusceptible to mucociliary expulsion.

Boric Acid

Any reference to “boric acid” herein includes the various sources andforms described below.

Boric acid, B(OH)₃, found in nature as the mineral sassolite, is anextremely weak acid (pK_(a)=9.24) with good water solubility (0.47 g/mL@20° C.). In aqueous solution at pH=7.4, free boric acid is the majorcomponent of a rapidly established equilibrium with hydronium borate:

B(OH)₃[98.4%]+2H₂O

H₃O⁺+B(OH)₄ ⁻[1.6%](pH=7.4)

(See, e.g., Woods (1994) Environ Health Perspect 102(Suppl 7):5-11.)

Borax, Na₂[B₄O₅(OH)₄], found in nature as the mineral colemanite, isalso in pH-dependent equilibrium with boric acid and borate in aqueoussolutions. Thus, aqueous boric acid-borax mixtures form a well-knownbuffer system that is useful over the pH range=7.4-9.7:

(See, e.g., Coddington and Taylor (1989) J Coord Chem 20(1):27-38.)Bacteriostatic and Fungistatic Properties of Boric Acid

Aqueous solutions of boric acid or borax are known to rapidly andreversibly form borate ester complexes with many hydroxyl-containingorganic compounds, especially monosaccharides (e.g., glucose, mannose,galactose, fructose, rhamnose, xylose, maltose, and lactose) andpolysaccharides (Deuel et al. (1948) Nature 161(4081):96.) Depending onthe number and conformation of free hydroxyl groups in the saccharide orpolysaccharide structure, sugar borate esters may form in a variety ofstoichiometries including well-known 2:1 sugar:borate Spiro complexes.In dilute aqueous solution, susceptible polysaccharides react with boricacid to give borate-polysaccharide chain complexes that may cross-linkto cause three-dimensional network formation and rapid gelification ofthe mixtures. In this context it is provocative that 2-3% aqueous boricacid has been observed to cause marked agglutination of Bacillusshiga-kruse (aka: Shigella dysenteriae) in agar culture. (Lopatkin(1940) Zhurnal Mikrobiologii, Epidemiologii i Immunobiologii 7:30-32.)S. dysenteriae is a Gram-negative species known to produce cell-wallpolysaccharides containing a high proportion of boric acid-reactiverhamnose. It was noted in this work, “No other acid, inorganic ororganic, gave this reaction.” Boric acid has also been shown to alterthe morphology of living Saccharomyces cerevisiae cells. (Schmidt et al.(2010) Int J Microbiol 2010; 2010:930465.)

An in vitro study of boric acid against cultured Candida albicansdemonstrated that 1% aqueous boric acid showed complete growthinhibition against 45 of the 46 fluconazole-susceptible strains testedand 24 of the 25 fluconazole-resistant strains tested. Using a focus setof six C. albicans strains the authors of this study were able toconvincingly eliminate pH as a primary basis for the fungistatic effectsof boric acid. No sign of sudden physical membrane damage was apparentand membrane integrity decreased only slightly during 24 hour exposureto 1% boric acid. (De Seta et al. (2009) J Antimicrob Chemother63(2):325-36.) This same study reported that 2.5% boric acid wassufficient for complete growth inhibition of 17 of 17 bacterial strainstested including Staphylococcus aureus (2 strains), Enterococcusfaecalis, Staphylococcus saprophyticus, Staphlyococcus epidermis,Bacillus sp., Streptococcus pyogenes, Streptococcus agalactiae,Citrobacter freundii, Enterobacter cloacae, E. coli (2 strains),Klebsiella pneumonia, Shigella sp., Proteus sp., Salmonella sp., andSerratia sp. (De Seta et al., supra.)

Microbial growth in urine samples while in transit to a pathologylaboratory is known to lead to significant time-dependent false positiveresults in medically important assays. However, microbiocidal treatmentof such samples is untenable because the pathogenic species present inthem subsequently need to be grown in culture for identification. Boricacid, 1.8-2%, has been known and used for decades as an efficientmicrobiostatic agent for transportation of urine samples containing awide range of bacterial and fungal pathogens. (Appannanavar et al.(2013) Indian J Pathol Microbiol 56(3):261-264; Brodie and

Porter (1971) Lancet 1(7690):133.) In controlled experiments using 17bacteria and fungi, the integrity of initial bacterial or fungal countswas maintained for all human pathogens studied for up to 24 hours at 24°C. (Meers and Chow (1990) J Clin Pathol 43(6):484-487.) Whensubsequently diluted out into appropriate nutrient culture media all ofthe preserved samples grew normally, demonstrating rapid and completereversibility of the bacteriostatic effect.

Methods of Treating Chronic Rhinosinusitis and Use of Boric AcidFormulations for Treating CRS

Boric acid is a very mild and well-tolerated topical bacteriostatic andfungistatic agent with very low potential for induction of microbialresistance in human pathogens. Whether applied in dilute solution orointment form on skin, or used in pure form on vaginal epithelium, boricacid shows little or no evidence of tissue irritation or other adverseevents in human subjects. Topical boric acid is not significantlyabsorbed across uninjured skin or vaginal epithelium; thus, thepotential for systemic exposure via topical applications to theparanasal epithelium may be correspondingly low.

The present invention is based on a demonstration that the underlyingcause and symptoms of microbial-related CRS disease can be amelioratedby intranasal delivery of a dilute boric acid solution followed byexsufflation and/or expectoration to clear mucus and excess boric acidsolution from the nasal and paranasal sinuses. The method comprisesadministering a formulation of boric acid to the nasal and paranasalcavities of a patient in need. The present invention also provides foruse of a formulation comprising boric acid for the treatment of chronicrhinosinusitis in a subject in need.

In either the method or use described and claimed herein, theformulation may comprise boric acid in an amount (weight per volume,w/v) from about 1.0-4.0%, particularly from about 1.0-2.5%. Inparticular embodiments, the formulation comprises boric acid in anamount of about 2.0% (w/v). The solvent for the formulation may be anysolvent having suitable characteristics of flowability for sufficientnasal and paranasal access, and compatibility with boric acid. Anexemplary solution that satisfies these requirements is a salinesolution, wherein the concentration (w/v) of sodium chloride (NaCl) inwater is from about 0.5-1.2%. In a particular embodiment theconcentration of sodium chloride in water is 0.9% (w/v), that is,isotonic saline. In one embodiment, the formulation comprises about 2%(w/v) of boric acid in a saline solution having about 0.9% (w/v) ofsodium chloride in water. Alternative solvents having characteristicssimilar to those of a saline solution as described above may be used inthe present formulations and are specifically encompassed by the presentinvention.

The formulation may be of a pH that is a natural result of formulatingthe desired amount of boric acid in an appropriate solvent, such as asaline solution.

The method of administering the boric acid formulation generallycomprises applying a volume of the formulation into each nare of thepatient in a manner sufficient to penetrate the nasal and paranasalcavities. The volume of the formulation may be administered by anyappropriate means known to those skilled in the art and include, but arenot limited to douching, nebulization, atomization, inhalation,irrigation, spray, drops, or insufflations. In particular embodiments, avolume of the formulation is administered by drops into each nare. Inanother particular embodiment, the volume of the formulation is appliedby spray into each nare. The invention specifically includes anembodiment wherein the formulation is a sterile, aqueous isotonicsuspension or solution of boric acid administered intranasally to thenasal-paranasal mucosa via spray pump. The various methods ofadministration may be and often are accompanied by maneuvering the head,and thereby the nasal and paranasal cavities, in a manner sufficient todistribute the formulation throughout the nasal and paranasal cavities.The method also may and often does include a subsequent step of clearingthe nasal and paranasal cavities of excess formulation by expectorationand/or exsufflation.

The volume of the formulation administered into each nare may vary butin all cases should be a volume sufficient to coat the nasal andparanasal cavities. In particular embodiments, the volume administeredto each nare is about 1-2 mL. Administration is generally based on needand may be repeated several times per day while symptoms are present. Inparticular embodiments, formulation is administered to the subject inneed 1-3 times per day.

A subject in need is a subject having symptoms consistent with chronicrhinosinusitis. In some embodiments, the subject has been diagnosed ashaving chronic rhinosinusitis. The subject having chronic rhinosinusitismay also have nasal polyps (CRSwNP) or be without nasal polyps (CRSsNP).In particular embodiments, the chronic rhinosinusitis ismicrobial-related CRS. In some embodiments, the chronic rhinosinusitisis bacterial-related. In some embodiments, the chronic rhinosinusitis isfungal-related.

EXAMPLES

The invention is further understood by reference to the followingexample, which is intended to be purely exemplary of the invention. Thepresent invention is not limited in scope by the exemplifiedembodiments, which are intended as illustrations of single aspects ofthe invention only. Any methods that are functionally equivalent arewithin the scope of the invention. Various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description. Suchmodifications fall within the scope of the appended claims.

The subject of the present example is a male who first presented withsymptoms of chronic rhinosinusitis in 1987. The subject was subsequentlydiagnosed with CRSwNP. No allergen was identified as a causative agent.Endoscopic surgery for removal of nasal polyps in 1987 was followed by ashort course of antibiotics and several systemic administrations ofcorticosteroids. A second surgery was required in December 1996 toremove recurring nasal polyps. This surgery was followed up with a shortcourse of oral antibiotics and daily intranasal corticosteroid (INS)therapy. The subject continued on INS therapy for about two years, butwith very little tangible relief of recurrent nasal congestion.

In 2012, the subject felt very distinctly like nasal polyps were onceagain recurring, i.e., the ball-valve sensation always from the sameside and especially when lying on one side. Upon this reoccurrence, thesubject prepared a sterile formulation of isotonic saline solutioncontaining 2% (w/v) of boric acid (Sigma catalog no. 15663; BioUltragrade (≧99.5%) assayed for ≦5 ppm of individual heavy metals). Theformulation was transferred into soft plastic squeeze bottles thatoriginally contained commercial saline for intranasal use.

The subject initially applied 1-2 mL of the boric acid formulation toeach nare about 2-3 times per day, tilting his head back to allowthorough irrigation of the sinuses and drainage into his mouth. Aftereach separate irrigation event, the subject expectorated, rinsed hismouth with fresh water, and blew his nose (exsufflated) to expel mucus.

Remission of the subject's CRS symptoms was rapid and profound. Duringthe first day or two of treatment, copious amounts of yellow ropy mucuswere expelled, followed by several more days of colorless and lessviscous mucus discharge. Within the first week, the subject was able tobreathe normally through his nasal sinuses for most of the day. Withinthree weeks of 2-3 treatments per day, the subject was free of thesensation of nasal congestion and was able to breathe normallyfull-time. Administration of the boric acid formulation was then reducedto “as-needed.”

A recent study of the bacterial constituents of the subject's nasalmucus by light microscopy at 1000×-1500× magnification was performed.The experiments consisted of boric acid lavages that were timedappropriately for before-and-after estimations of bacterial content froma “sneeze-on-a-slide.” test. The results were qualitatively clear that(1) the paranasal microbiome consisted mainly of (unidentified) cocci,(2) boric acid lavages acutely reduced the bacterial count dramatically,and (3) the microbiota was substantially replenished within 24-48 hoursof boric acid lavage.

Over the past 3 year treatment period, the subject has continued to usethis treatment on an “as-needed” basis, typically anywhere from 1-2times daily to 2 times per week, depending on symptoms.

The following is a summary of quality-of-life benefits that have accruedsince initiation of treatment for CRSwNP with 2% boric acid in saline:

The subject is no longer a “mouth-breather,” and has been able tobreathe normally through his nose for the past three years.

The annoying “ball-valve” sensation that the subject feared might signalthe return of nasal polyposis completely ceased within a few months ofself-treatment initiation.

Within a month or so of treatment initiation, the subject was able tosleep comfortably without the aid of a dental appliance for the firsttime in approximately a decade. Episodes of snoring and explosiveepisodes of sleep apnea have diminished or ceased entirely.

The subject's sense of smell returned to an astonishing degree withinthe first year or so of treatment.

Although the subject has had a few colds over the past 3 years, he hasnot experienced any painful acute sinus infections since beginningtreatment with boric acid.

The subject also reports that the frequency and severity of occasionalheadaches has decreased over the past 3 years of CRS self-treatment.

Various modifications of the invention, in addition to those shown anddescribed herein, will become apparent to those skilled in the art fromthe foregoing description. Such modifications are intended to fallwithin the scope of the appended claims.

All references cited herein are hereby incorporated by reference hereinin their entirety.

What is claimed is:
 1. A method of treating chronic rhinosinusitis, themethod comprising administering a formulation comprising boric acid tothe nasal and paranasal cavities of a patient in need, thereby treatingthe chronic rhinosinusitis.
 2. The method of claim 1, wherein theformulation comprises about 1.0-4.0% (w/v) of boric acid.
 3. The methodof claim 1, wherein the formulation comprises about 2.0% (w/v) of boricacid.
 4. The method of claim 1, wherein the formulation furthercomprises a saline solution having about 0.5-1.2% (w/v) of sodiumchloride in water.
 5. The method of claim 1, wherein the formulationfurther comprises a saline solution having about 0.9% (w/v) of sodiumchloride in water.
 6. The method of claim 1, wherein the formulationcomprises about 2% (w/v) of boric acid in a saline solution having about0.9% (w/v) of sodium chloride in water.
 7. The method of claim 1,wherein the administering comprises applying a volume of the formulationinto each nare of the patient in a manner sufficient to penetrate thenasal and paranasal cavities.
 8. The method of claim 7, wherein thevolume of the formulation is applied by a means selected from the groupconsisting of douching, nebulization, atomization, inhalation,irrigation, spray, drops, or insufflations.
 9. The method of claim 7,wherein the volume of the formulation is applied by spray pump.
 10. Themethod of claim 1, wherein the formulation is a sterile, aqueousisotonic suspension or solution administered intranasally to thenasal-paranasal mucosa via spray pump.
 11. The method of claim 7,wherein the volume of the formulation administered into each nare isabout 1-2 mL.
 12. The method of claim 1, wherein the chronicrhinosinusitis is bacterial-related.
 13. The method of claim 1, whereinthe chronic rhinosinusitis is fungal-related.
 14. The method of claim 1,wherein the patient has chronic rhinosinusitis with nasal polyps. 15.The method of claim 1, wherein the patient has chronic rhinosinusitiswithout nasal polyps.